目的 研究淫羊藿中的主要活性成分淫羊藿苷元在大鼠体内的血浆动力学和组织分布特征，为黄酮类天然药物的开发提供依据。方法 应用高效液相色谱-串联质谱（HPLC-MS/MS）测定大鼠血浆及组织中游离淫羊藿苷元（淫羊藿苷元原型）和总淫羊藿苷元（淫羊藿苷元原型及其二相代谢产物的总和）的浓度，并应用WinNonlin 7.0软件非房室模型计算药动学参数。结果 大鼠iv淫羊藿苷元（5 mg/kg）后，血浆中游离淫羊藿苷元和总淫羊藿苷元的血药峰浓度（C_max）分别为（978±107）、（2390±295）ng/mL，血药浓度-时间曲线下面积（AUC_0-t）分别为（422±38）、（3000±932）ng·h/mL，消除半衰期（t_1/2）分别为（1.640±0.767）、（3.82±2.16）h。大鼠ig淫羊藿苷元（10 mg/kg）后，血浆中游离型淫羊藿苷元及总淫羊藿苷元的达峰时间（T_max）为0.292 h，C_max分别为（12.90±5.77）、（3800±1110）ng/mL，AUC_0-t分别为（12.00±8.01）、（5760±2200）ng·h/mL，t_1/2分别为（0.812±0.263）、（2.73±1.28）h。大鼠ig淫羊藿苷元（10 mg/kg）后，游离淫羊藿苷元在组织中的分布程度由高到低排序依次为胃、肠、肺（110~220倍血浆）、肝、子宫（20~65倍血浆）、心、卵巢、脾（4~15倍血浆）、骨髓、肾、肌肉（1~2倍血浆）、血浆、脑、脂肪（20%~50%血浆）、睾丸（未检测到）；总淫羊藿苷元在组织中的分布由高到低排序依次为肠、胃、肺（1~2倍血浆）、血浆、肝、肾、子宫、卵巢（20%~60%血浆）、肌肉、心、脾、睾丸、骨髓、脂肪、脑（1%~7%血浆）。结论 大鼠ig给药后，血浆中游离淫羊藿苷元及总淫羊藿苷元吸收迅速，消除较快，与iv给药相比，游离淫羊藿苷元的绝对生物利用度仅为1.42%，而总淫羊藿苷元绝对生物利用度达到96.0%。血浆中游离淫羊藿苷元的暴露量明显低于总淫羊藿苷元，仅占总淫羊藿苷元暴露量的0.208%，提示淫羊藿苷元ig给药后在大鼠血液循环系统中主要以II相结合型产物暴露为主。但在多数组织中游离淫羊藿苷元的暴露量、暴露持续时间均明显高于血浆，而且游离淫羊藿苷元与总淫羊藿苷元的比例也明显大于血浆。

Objective To describe the pharmacokinetics and tissue distribution of icaritin in rats and provide supports for further development of natural flavonoids. Methods The concentrations of free (icaritin) and total icaritin (the sum of icaritin and its two phase metabolites) in rats were detected by HPLC-MS/MS, the pharmacokinetic parameters were calculated by WinNonlin 7.0 with non-compartment model. Results After intravenous injection of icaritin (5 mg/kg) in rats, the C_max of free and total icaritin in plasma were (978±107) and (2390±295) ng/mL, respectively; AUC_0-t of which were (422±38) and (3000±932) ng·h/mL, respectively, t_1/2 were (1.640±0.767) and (3.82±2.16) h, respectively. After intragastric administration of icaritin (10 mg/kg) in rats, the t_max of free and total icaritin in plasma were about 0.292 h, C_max were (12.90±5.77) and (3800±1110) ng/mL, respectively; AUC_0-t were (12.00±8.01) and (5760±2200) ng·h/mL, respectively, the results of t_1/2 were (0.812±0.263) and (2.73±1.28) h, respectively; After intragastric administration of icaritin (10 mg/kg) in rats, the distribution of free icaritin in tissues in the order from high to low as follows:stomach, intestine, lung (110-220 times of plasma), liver, uterus (20-65 times of plasma), heart, ovary, spleen (4-15 times of plasma), bone marrow, kidney, muscle (1-2 times of plasma), plasma, brain, fat (20%-50% plasma), testicle (not detected). The distribution of total icaritin in tissues in the order from high to low as follows:intestine, stomach, lung (1-2 times of plasma), plasma, liver, kidney, uterus, ovary (20%-60% plasma), muscle, heart, spleen, testicle, bone marrow, fat, brain (1%-7% plasma). Conclusion After intragastric administration, the free and total icaritin in plasma were absorbed and eliminated rapidly, compared with intravenous administration, the absolute bioavailability of free icaritin was only 1.42%, while that of total icaritin was 96.0%. In plasma, the exposure of free icaritin was lower than that of total icaritin, the ratio of free icaritin to total icaritin exposure (AUC) was about 0.208%, which suggested that icaritin was mainly exposed as II binding products in the blood circulation system of rats. However, the exposure amount and exposure time of free icaritin in most tissues were significantly higher than those in plasma, and the ratio of free icaritin to total icaritin was significantly higher than that in plasma.

R285

中国医学科学院医学与健康科技创新工程项目（2019-I2M-5-020）；释药技术与药代动力学国家重点实验室（天津药物研究院）自主研究课题（010161005）